Despite the widespread use of bone grafts in reconstructive trauma and total joint surgery, the physiological and biological events that are crucial to the process of incorporation and the mechanisms that control these actions are only superficially understood. It is known that incorporation requires cooperative interactions between the recipient site and the bone graft, each providing unique and indispensable contributions. Fresh autogenous or syngeneic grafts are considered the "gold standard"; they are revascularized early, stimulate orderly new bone formation, and become integrated mixtures of original and new bone. Our previous in vivo work has shown that both the freezing of a graft and immunogenicity of a graft are deleterious to the process of graft incorporation. Graft cells do not survive freezing: freezing of syngeneic grafts retards revascularization by several months and delays early new bone formation. Allogeneic grafts are poorly revascularized, stimulate poorly organized new woven bone formation, and never become integrated mixtures of original and new bone. By four weeks after surgery, the differences between fresh syngeneic grafts and frozen or allogeneic grafts are already apparent. These in vivo findings imply that critical interactions occur between the host and the graft during the first few weeks following implantation. Therefore, we propose the hypothesis that early interactions between the cells of a bone graft and the cells of the host inflammatory/wound healing/immune response determine the ultimate revascularization, incorporation and substitution of a cortical graft. The optimum revascularization, incorporation and substitution occur when a normal inflammatory response is invoked in the absence of a specific immune response and the cells of that response interact with living cells of the bone graft. Monocytes/macrophages, lymphocytes, and bone cells all synthesize, release and respond to interleukin 1 (IL-1), transforming growth factor beta (TGF-B), tumor necrosis factor alpha (TNF-A), and prostaglandin E2 (PGE2). We speculate that bidirectional actions of these mediators modulate healing, revascularization, immune responses, and bone physiology. Our proposed in vivo cage model, which is a standard model for the study of normal inflammation and wound healing, isolates the graft in a realistic environment which allows host-graft interactions as well as sequential sampling of the cells and fluid surrounding the graft. We will test our hypothesis by defining the host response to fresh syngeneic grafts and then comparing the response to allogeneic grafts and to frozen grafts to that of fresh syngeneic grafts. We predict that the responses to allogeneic and frozen grafts will differ significantly from those elicited by fresh syngeneic grafts. Knowledge of the early sequence of host-graft interactions that leads to a known positive outcome (fresh syngeneic graft) and clarification of variations in the sequence that lead to delayed or poor outcome (frozen or allogeneic grafts) may permit therapeutic cytokine intervention in graft incorporation.